U.S. patent number 7,128,067 [Application Number 10/394,654] was granted by the patent office on 2006-10-31 for method and apparatus for generating an aerosol.
This patent grant is currently assigned to Philip Morris USA Inc.. Invention is credited to Peter R. Byron, Michael Hindle.
United States Patent |
7,128,067 |
Byron , et al. |
October 31, 2006 |
Method and apparatus for generating an aerosol
Abstract
An aerosol is formed by supplying a material in liquid form to a
flow passage and heating the flow passage such that the material
volatizes and expands out of an open end of the flow passage. The
volatized material combines with ambient air such that volatized
material condenses to form the aerosol. An apparatus and method for
generating such an aerosol are disclosed wherein the apparatus may
include an electrically conductive sleeve at an open end of the
flow passage, an electrically conductive flow passage and/or a
spacer chamber. The volatilized material may contain a volatilized
solute and vehicle such that the resulting aerosol particle sizes
of the solute and the vehicle are either different or the same.
Inventors: |
Byron; Peter R. (Richmond,
VA), Hindle; Michael (Glen Allen, VA) |
Assignee: |
Philip Morris USA Inc.
(Richmond, VA)
|
Family
ID: |
24238095 |
Appl.
No.: |
10/394,654 |
Filed: |
March 24, 2003 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20040016427 A1 |
Jan 29, 2004 |
|
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
09560510 |
Apr 27, 2000 |
|
|
|
|
Current U.S.
Class: |
128/200.14;
222/146.3; 516/8; 128/204.17; 128/203.17 |
Current CPC
Class: |
A61M
11/041 (20130101); A61M 11/042 (20140204); A61M
16/109 (20140204); A61M 11/007 (20140204); A61M
2016/0024 (20130101); A61M 2205/8206 (20130101) |
Current International
Class: |
A61M
15/00 (20060101); B67D 5/62 (20060101); H05B
3/00 (20060101) |
Field of
Search: |
;128/200.14-200.24,203.12,203.14,203.21,203.17,203.23,203.27,203.26,204.17,204.21,204.23,207.14,207.18 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
354004 |
|
Sep 1928 |
|
BE |
|
354094 |
|
Sep 1928 |
|
BE |
|
1036470 |
|
Aug 1958 |
|
DE |
|
0358114 |
|
Mar 1990 |
|
EP |
|
0642802 |
|
May 1996 |
|
EP |
|
667979 |
|
Oct 1929 |
|
FR |
|
168128 |
|
Nov 1977 |
|
HU |
|
216121 |
|
Mar 1991 |
|
HU |
|
207457 |
|
Apr 1993 |
|
HU |
|
P953409 |
|
Jun 1994 |
|
HU |
|
94/09842 |
|
May 1994 |
|
WO |
|
98/17131 |
|
Apr 1998 |
|
WO |
|
01/12319 |
|
Mar 2001 |
|
WO |
|
01/43800 |
|
Jun 2001 |
|
WO |
|
01/81182 |
|
Nov 2001 |
|
WO |
|
Other References
Byron, Peter R. Ph.D., Chairman, "Recommendations of the USP
Advisory Panel on Aerosols on the USP General Chapters on Aerosols
(601) and Uniformity of Dosage Units (905)", Pharmacopeial Forum,
vol. 20, No. 3, pp. 7477-7505, May-Jun. 1994. cited by other .
Hou, Shuguang et al. Solution Stability of Budensonide in Novel
Aerosol Formulations Abstract No. 2582, Solid State Physical
Pharmacy, Nov. 17, 1998, p. S-307. cited by other .
Kousaka, Yasuo et al., "Generation of Aerosol Particles by Boiling
of Suspensions", Aerosol Science and Technology, 21:236-240 (1994).
cited by other .
Roth, G. et al. High Performance Liquid Chromatographic
Determination of Epimers, Impurities, and Content of the
Glucocorticoid Budesonide and Preparation of Primary Standard,
Journal of Pharmaceutical Sciences, vol. 69, No. 7, pp. 766-770,
Jul. 1980. cited by other .
Written Opinion dated Dec. 24, 2003 for PCT/US02/30871. cited by
other .
Notification of Transmittal of International Preliminary
Examination Report dated Apr. 29, 2004 for PCT/US02/30871. cited by
other .
Benjamin, Y. H. Liu et al., "A Condensation Aerosol Generator for
Producing Monodispersed Aerosols in the Size Range 0.036.mu. to
1.3.mu.", Journal De Recherches Atmospheriques, 1996, pp. 397-406.
cited by other.
|
Primary Examiner: Dawson; Glenn K.
Attorney, Agent or Firm: Buchanan Ingersoll & Rooney
PC
Parent Case Text
This application is a continuation of application Ser. No.
09/560,510, filed on Apr. 27, 2000 now abandoned.
Claims
What is claimed is:
1. A method of generating an aerosol containing budesonide,
comprising: supplying a liquid containing a suspension of propylene
glycol and particles consisting essentially of budesonide to a flow
passage; heating the liquid in the flow passage such that the
liquid is volatilized and expands out of an open end of the flow
passage and forms a propylene glycol aerosol of aerosolized
budesonide having a mass median aerosol diameter (MMAD) of 2 .mu.m
or less, wherein the liquid includes propylene glycol and the
aerosol includes aerosolized propylene glycol having a larger MMAD
than the aerosolized budesonide.
2. The method of claim 1, wherein the flow passage is an
electrically conductive flow passage and the heating is carried out
by passing electrical current through the electrically conductive
flow passage.
3. The method of claim 1, wherein the liquid is supplied from a
source which creates a back pressure of at least 20 psi while the
liquid is heated.
4. The method of claim 1, wherein the flow passage is a capillary
passage.
5. The method of claim 1, wherein the liquid is supplied
continuously to the flow passage.
6. The method of claim 1, wherein the heating occurs upon
breath-actuation of a hand-held inhaler incorporating the flow
passage therein.
7. The method of claim 1, wherein the aerosol is formed in a
mouthpiece of a hand-held inhaler.
8. The method of claim 1, wherein the aerosol is formed by
condensation of the volatilized liquid.
9. The method of claim 1, wherein the aerosol is formed in a spacer
chamber of a hand-held inhaler.
10. The method of claim 1, wherein the flow passage includes an
electrically conductive sleeve at the open end, the conductive
sleeve being effective to provide a narrow particle size
distribution of the aerosol.
11. The method of claim 1, wherein the liquid is supplied to the
flow passage at a rate of at least 1 milligram/second.
12. The method of claim 1, wherein the liquid consists of solid
budesonide particles suspended in propylene glycol.
13. The method of claim 1, wherein the method results in a
theoretical recovery of at least about 73%.
Description
The present invention relates generally to an apparatus and method
for generating aerosols without compressed gas propellants.
BACKGROUND OF THE INVENTION
Aerosols are useful in a wide variety of applications. For example,
it is often desirable to treat respiratory ailments with, or
deliver medicaments by means of, aerosol sprays of finely divided
particles of liquid and/or solid, such as powders, liquid
medicaments, and the like, which are inhaled into a patient's
lungs. Aerosols are also used for such purposes as providing
desired scents to rooms, applying scents to the skin, and
delivering paint and lubricant, for example.
Various techniques are known for generating aerosols, particularly
in the field of medicine. For example, U.S. Pat. Nos. 4,811,731 and
4,627,432 both disclose devices for administrating medicaments to
patients in which a capsule is pierced by a pin to release
medicament in powder form. The user inhales released medicament
through an opening in the device. Medicaments in liquid form are
known to be delivered by generation of an aerosol with a manually
operated pump. The pump draws liquid from a reservoir and forces it
through a small nozzle opening to form a fine spray.
Both of these methods of generating an aerosol for the delivery of
medicaments suffer from problems. The aerosols produced by these
techniques contain substantial quantities of particles or droplets
which are too large to be inhaled. Further, it is difficult to
synchronize the inhalation of the medicament with the pumping of
the aerosol device or the release of the powder. Persons who have
difficulty in generating a sufficient flow of air through the
device to properly inhale the medicaments, such as asthma or
emphysema sufferers, have particular difficulty in using these
devices.
An alternate means of delivering a medicament is generating an
aerosol including liquid or powder particles by means of a
compressed propellant, usually a chloro-fluoro-carbon (CFC) or
methyl chloroform, which entrains the medicament, usually by the
Venturi principle. Such inhalers are usually operated by depressing
a button to release a short charge of the compressed propellant
which contains the medicament through a spray nozzle, allowing the
propellant encapsulated medicament to be inhaled by the user.
However, it is again difficult to properly synchronize the
inhalation of the medicament with depression of the actuator.
Further, large quantities of medicament or other materials are not
suitably delivered by this method. This method is better suited to
delivery of such materials as antiperspirants, deodorants and
paints, for example.
Most known aerosol generators also are unable to generate aerosols
having an average mass median aerosol diameter (MMAD) less than 2
to 4 microns, and are incapable of delivering high flow rates, such
as above 1 milligram per second, with particles in the range of 0.2
to 2.0 microns. A high flow rate and small particle size are
particularly desirable for better penetration of the lungs during
medicament administration, such as for asthma treatment.
Large particles generated by aerosol generators may be deposited in
the mouth and pharynx of the patient, rather than inhaled into the
lungs. Further, what is inhaled may not penetrate the lungs deeply
enough. Therefore, it is known to add a spacer chamber to a
pressurized inhaler mechanism in order to allow the propellant time
to evaporate, decreasing the mass median aerosol diameter of the
particles. See, for example, U.S. Pat. No. 5,855,202 to Andrade and
Eur. Respir. J. 1997; 10:1345 1348. Particles from aerosol
generators may have an MMAD of 5 6 .mu.m. The use of a spacer
chamber in such a case reduces the particle MMAD to about 1.5 .mu.m
or greater, enhancing medicament deposition in the lung as opposed
to the mouth or throat. See, for example, Eur. Respir. J. 1997,
10:1345 1348; International Journal of Pharmaceutics, 1 (1978) 205
212 and Am. Rev. Respir. Dis. 1981, 124:317 320.
Spacer chambers also are known to affect the output of the aerosol
device because of the static charge which may be created therein.
Medicament particles may be deposited in spacer chambers by
electrostatic attraction to the spacer chamber wall, by inertial
impaction, or by gravitational settling over time. Further,
different medicaments behave differently within such spacer
chambers based on particle size, particle charge, and the like.
Thus, loss of medicament occurs within spacer chambers and is a
drawback to effective spacer chamber use. See Eur. Respir. J. 1997;
10: 1345 1348.
The aerosol generator (CAG) described in U.S. Pat. No. 5,743,251,
herein incorporated by reference, and further described in
Respiratory Drug Delivery VI, Eds. R. N. Dalby et al., Interpharm
Press, IL (1998) pp 97 102, has many advantages over other aerosol
generators. In general, the CAG operates by supplying a material in
liquid form to a flow passage, such as a tube or capillary, and
heating the flow passage so that the material volatilizes and
expands out of the open end of the flow passage. The volatilized
material combines with ambient air in such a manner that the
volatilized material condenses to form an aerosol. The aerosol
therefore contains no propellant, and has a mass median aerosol
diameter of less than about 2 microns, generally between about 0.2
and about 2 microns, and preferably between about 0.2 and about 1
micron.
However, like other aerosol generators, some material can be lost
during aerosol generation to the CAG device itself. It has been
found that some aerosol particles can deposit on the end of the
capillary or tube, thereby retaining the aerosol particles within
the device itself. This phenomenon appears in part to be solute
dependent. Further, if used to deliver medicament to the lungs of a
patient, some aerosolized medicament can be lost to the throat and
mouth of the patient. Because the CAG produces very fine particles,
the particles may potentially be exhaled before settling fully into
the patient's lungs, diminishing the amount of medicament delivered
to the patient.
It is desirable to achieve a particle size of an aerosol which can
penetrate deep into the lungs. It is further desirable to have the
same or approximately the same mass median aerosol diameter for the
aerosolized liquid and solid components. Further, it is desirable
to minimize loss of the aerosol to the aerosol generator, as well
as to the mouth and throat of the patient. One or more of these
attributes can be achieved by the methods and apparatus described
herein.
SUMMARY OF THE INVENTION
In accordance with one preferred embodiment of the present
invention, the flow passage of the aerosol generator can be coated
at the open end with an electrically conductive substance, such as
a metal. In a second preferred embodiment, the flow passage can be
made entirely of an electrically conductive material, such as
stainless steel.
In accordance with another embodiment of the present invention, a
spacer chamber can be added at the open end of the flow passage.
Such a spacer chamber facilitates the enlargement of the mass
median aerosol diameter of the aerosol particles generated.
In accordance with yet another embodiment of the present invention,
an aerosol can be provided wherein the mass median aerosol diameter
of the liquid and solid components of the aerosol are approximately
equal, such as in the case where the aerosol is generated from a
mixture of budesonide in triethylene glycol.
In accordance with yet another embodiment of the present invention,
an aerosol can be provided wherein the MMAD of the liquid and solid
components of the aerosol are different, such as in the case where
the aerosol is generated from a mixture of budesonide in propylene
glycol.
BRIEF DESCRIPTION OF THE DRAWINGS
The features and advantages of the present invention are well
understood by reading the following detailed description in
conjunction with the drawings in which like numerals indicate
similar elements and in which:
FIG. 1 is a schematic view of an aerosol generator according to a
first embodiment of the present invention;
FIG. 1A is a schematic view of an aerosol generator according to a
second embodiment of the present invention;
FIGS. 2A and 2B are schematic views of a portion of an aerosol
generator including heaters according to embodiments of the present
invention;
FIG. 3 is a schematic view of an aerosol generator according to a
third embodiment of the present invention;
FIG. 4 is a schematic view of an aerosol generator according to a
fourth embodiment of the present invention;
FIG. 5 is a graph showing increase in particle size with use of a
spacer chamber;
FIG. 6 is a graph showing increase in particle size over time with
use of a spacer chamber;
FIG. 7 is a second graph showing increase in particle size over
time with use of a spacer chamber;
FIG. 8 is a graph showing increase in particle size with decreasing
spacer chamber volume;
FIG. 9 is a graph showing the effects of holding time on the
particle size of propylene glycol using spacers of various
sizes;
FIG. 10 is a graph showing increase in budesonide particle size
with decreasing spacer chamber volume;
FIG. 11 is a graph of particle size following aerosol generation
from solutions of benzil in propylene glycol, and budesonide in
propylene glycol, respectively;
FIG. 12 is a graph of particle size following aerosol generation
from solutions of budesonide in propylene glycol and budesonide in
triethylene glycol;
FIGS. 13(a) (d) are graphs depicting particle size of aerosols from
(a) benzil in propylene glycol, (b) benzil in triethylene glycol,
(c) budesonide in propylene glycol, and (d) budesonide in
triethylene glycol; and
FIGS. 14A and B are a depiction of the general experimental
apparatus used to test aerosols and determine their particle
size.
DETAILED DESCRIPTION
An aerosol generator will be described in preferred embodiments
wherein the usage is for medicament administration, particularly to
the lungs of a person such as someone suffering from asthma,
emphysema or other like disorders.
An aerosol generator 21 according to a first embodiment of the
present invention is schematically shown with reference to FIG. 1.
The aerosol generator 21 includes a flow passage 23 having an open
end 25. A heater 27 is positioned adjacent to at least a portion of
the flow passage 23, but preferably in a way that provides a heated
zone around the flow passage that maximizes heat transfer
throughout the heated zone. The heater 27 is connected to a power
supply 29, preferably a D.C. power supply such as a battery.
In operation, a material (not shown) in liquid form is introduced
to the flow passage 23. The heater 27 heats the portion of the flow
passage 23 to a sufficient temperature to volatilize the liquid
material. In the case of an organic liquid material, the heater
preferably heats the liquid material just to the boiling point of
the liquid material, and preferably maintains the surface
temperature of the flow passage 23 below 400.degree. C., as most
organic materials are not stable when they are exposed to
temperatures above that temperature for periods of time. The
volatilized material expands out of the open end 25 of the flow
passage 23. The volatilized material mixes with ambient air outside
of the flow passage and condenses to form particles, thereby
forming an aerosol.
In a presently preferred embodiment, the flow passage 23 is a
capillary or tube, or a portion thereof. The flow passage 23 is
preferably about 1.4 to 1.5 cm long and has an inside diameter of
between 0.05 and 0.53 millimeter. A particularly preferred inside
diameter of the flow passage is approximately 0.1 millimeter. The
wall thickness is preferably about 0.0025 inch (0.064 mm). Those
skilled in the art will recognize that flow passages of other
parameters may be used dependent on many factors, such as the
overall size of the aerosol generator desired, the material to be
volatilized, the amount of material to be delivered, and the like.
The flow passage 23 is preferably a portion of a fused silica
capillary tube or an aluminum silicate ceramic capillary tube.
However, other substantially non-reactive materials capable of
withstanding repeated heating cycles and generated pressures and
having suitable heat conduction properties may also be used.
The flow passage 23 preferably has an electrically conductive
sleeve 26 surrounding it at the open end 25. The sleeve 26 is
preferably stainless steel, though other electrically conductive
materials may be used, for example, copper, aluminum and the like.
It is preferred that the material of the sleeve 26 is capable of
withstanding repeated heating cycles and generated pressures and
has suitable heat conduction properties. It is preferable that the
sleeve is also non-reactive with the vaporized liquid. The addition
of an electrically conductive sleeve 26 diminishes medicament
deposition at the open end 25 of the flow passage 23, and further
has been found to improve the particle size distribution of the
aerosol such that the deposition of medicament in the lungs is
improved when the aerosol generator is used to deliver medicament.
The sleeve 26 can be sized to accommodate the flow passage, e.g., a
sleeve approximately 2 mm in length with a 24 gauge internal
diameter and wall thickness of about 0.005 inch (0.13 mm) fitted
over the capillary tube at the open end. One skilled in the art
will recognize that the dimensions of the sleeve can be varied in
accordance with those of the flow passage.
According to another embodiment, the entire flow passage 23 can be
constructed of an electrically conductive material, such as
stainless steel. Again, other electrically conductive materials can
be used so long as they are non-reactive, and capable of
withstanding repeated heating cycles and generated pressures and
have suitable heat conduction properties. An electrically
conductive flow passage 23 further reduces deposition at the open
end 25 of the flow passage 23, thus reducing deposition within the
aerosol generator and altering the aerosol particle size
distribution in such a way as to minimize deposition within the
mouth and throat of a patient using the aerosol generator for
medicament administration. If desired or necessary, an inside wall
of the flow passage 23 may be provided with a coating for reducing
the tendency of material to stick to the wall of the flow passage,
thereby minimizing clogging of the flow passage.
The deposition of material at the open end 25 of the flow passage
23 appears to be material specific. For example, medicaments with
low volatility appear to coagulate more at the open end 25 of the
flow passage 23, elsewhere within the aerosol generator and may
coagulate in the mouth and throat of a patient to whom the
medicament is administered. While not wishing to be bound by
theory, it is believed that the medicament or other material may
form an electrostatic charge during aerosol condensation. Use of an
electrically conducting material around the open end 25 of the flow
passage 23, or for the flow passage 23 itself, is believed to
discharge the electrostatic charge, leaving neutral medicament
particles. This allows for a more even distribution of the
particles and prevents attraction of the particles to surfaces of
the aerosol generator and to the patient's mouth and throat due to
static electricity, thereby lowering overall loss of the aerosol
before reaching the desired target site. However, the flow passage
23 preferably does not impart an electric charge to the particles,
but rather removes an electric charge, making the particles neutral
at the time they exit the open end 25 of the flow passage 23.
The flow passage 23 may be closed at a second end 31 and material
in liquid form may be introduced into the flow passage 23 through
the open end 25 when it is desired to form an aerosol. Thus, when
the liquid material is heated by the heater 27, the volatilized
material is only able to expand by exiting the flow passage 23
through the open end 25. However, it is preferred that the second
end 31 of the flow passage be connected to a source 33 (shown by
dotted lines in FIG. 1) of liquid material. The liquid material
volatilized by the heater 27 in the portion of the flow passage 23
is prevented from expanding in the direction of the second end 31
of the flow passage, and is forced out of the open end 25 of the
flow passage, as a result of back pressure of liquid from the
source 33 of liquid material. The back pressure of the liquid is
preferably between about 20 to 30 psi.
The heater 27 is preferably an electrical resistance heater.
According to a preferred embodiment, the heater 27 is a heater wire
having an outside diameter of 0.008 inches, a resistance of 13.1
ohms per foot, and a specific heat of 0.110 BTU/lb .degree. F. The
composition of the heater wire is preferably 71.7% iron, 23%
chromium, and 5.3% aluminum. Such a heater wire is available from
Kanthal Furnace Products, Bethel, Conn. One skilled in the art will
recognize other heater parameters and materials which may be used
dependent upon the size of the aerosol generator, the material
composition of the flow passage, the heat needed to volatilize the
desired material in liquid form, and the like.
According to another preferred embodiment, the heater 27A and 27B
shown in FIGS. 2A and 2B, respectively, includes a thin platinum
layer 27A'. and 27B', respectively, which is deposited on the
outside of a lapped ceramic capillary flow passage 23 serving as a
substrate. In addition to the aluminum silicate ceramic capillary
noted above, the flow passage may include a ceramic such as
titania, zirconia, or yttria-stabilized zirconia which does not
experience oxidation at normal operating temperatures after
repeated cyclings. Preferably the ceramic of the flow passage is
alumina having approximately a 99% purity, and more preferably
approximately a 99.6% purity, such as is available from the Accumet
Engineering Corporation of Hudson, Mass.
The flow passage and the heater layer preferably have a roughly
matching coefficient of thermal expansion to minimize thermally
induced delamination. The ceramic has a determined roughness to
affect the electrical resistance and to achieve adhesion of the
deposited platinum layer. The platinum layer does not experience
oxidation degradation or other corrosion during projected life
cycles.
The thin film heater layer is deposited on the flow passage 23. The
heater layer is preferably a thin platinum film having a thickness
of, e.g., less than approximately 2 .mu.m, though other thicknesses
may be used. The heater layer is deposited onto the capillary by
any suitable method such as DC magnetron sputter deposition, e.g.,
using an HRC magnetron sputter deposition unit, in argon at
8.0.times.10.sup.-3 Torr. Alternatively, other conventional
techniques such as vacuum evaporation, chemical deposition,
electroplating, and chemical vapor deposition are employed to apply
the heater layer to the flow passage.
The surface morphology of the flow passage substrate, particularly
of a ceramic capillary, is important to accomplish a successful
deposition of the heater layer. Preferably, the flow passage 23 is
lapped by a conventional serrated knife. Typical lapped alumina has
an unpolished surface roughness between approximately 8 and 35
microinches. The ceramic flow passage substrate is then polished to
a surface roughness having an arithmetic average greater than
approximately one microinch and, more specifically, between one and
approximately 100 microinches, and most preferably between 12 and
22 microinches. If the substrate is polished to further reduce
surface roughness as in conventional ceramic substrate preparation,
i.e., to a surface roughness of one microinch or less, an adequate
deposition interface will not be formed.
As seen in FIG. 2A, the heater layer 27A' is coupled to the power
supply by means of appropriate contacts 27A'' for resistive heating
of the heater layer. As seen in FIG. 2B, the heater layer 27B' is
coupled to the power supply by conductive posts 27B'' for resistive
heating of the heater layer. The contacts or posts preferably have
a lower resistance than the associated heater layer to prevent or
reduce heating of these connections prior to heating of the heater
layer. As seen in FIG. 2A, the contacts 27A'' may comprise a gold
coated tungsten wire, such as a W-wire wool (commercially available
from the Teknit Corporation of New Jersey) which is gold coated.
Alternatively, the contacts may comprise copper leads. The contacts
27A'' contact the platinum heater layer 27A' on or in the heater
layer top surface or at any other location so long as an adequate
electrical contact is achieved. The contacts 27A' may be
electrically connected to mounds 28A' of the platinum heater layer
27A', the heater layer further having an active area 28A'' for
heating the flow passage 23 therebetween. The resistance of the
heater layer 27A' is affected by the morphology of the flow passage
23.
As seen in FIG. 2B, electrically conductive contact posts 27B'' may
be used instead of the above-described contact arrangements and may
be formed to improve the mechanical strength of the assembly. The
contact posts are connected to the outside of the flow passage 23
prior to deposition of the heater layer 27B' and are connected to
the power supply by means of wires. The contact posts may be
comprised of any desired material having good electrical
conductance such as copper or copper alloys such as phosphur bronze
or Si bronze, and are preferably copper or any alloy having at
least approximately 80% copper. The posts 27B'', or a bonding
layer, as discussed below, provide a low electrical resistance
connection for use with a desired current. If copper or a copper
alloy is not employed for the posts, then preferably an
intermediate copper bonding layer (not shown) is connected by any
conventional technique to the end of the post to permit bonding
between the post and the flow passage 23 without affecting the
electrical path.
The connection of the ends of the posts 27B'' to the flow passage
23 is preferably achieved by eutectic bonding wherein a surface of
copper is oxidized, the resulting copper oxide surface is contacted
with the ceramic flow passage substrate, the copper-copper oxide is
heated to melt the copper oxide but not the copper such that the
melted copper oxide flows into grain boundaries of the ceramic, and
then the copper oxide is reduced back to copper to form a strong
bond. This connection can be achieved by a eutectic bonding process
such as used by Brush Wellman Corporation of Newbury Port,
Mass.
Next, the platinum heater layer 27B' is applied to the ceramic flow
passage 23. The heater layer comprises an initial layer 27C'
extending around the flow passage 23 and the posts 27B'' and a
contact layer 27D' which electrically connects the posts to the
initial layer. The active heating area 28B'' is defined on the
portion of the heater layer 27B' which is not covered by the
contact layer 27D' as a result of masking the heating area prior to
applying the contact layer. Mounds or thick regions 28B' are formed
by the contact layer 27D' around the posts 27B'' and rise from the
flow passage surface to function as contacts. In the embodiments
illustrated in FIGS. 2A and 2B, by providing mounds or graded
regions of platinum in the heater layer such that it is thicker at
the contacts or posts than at the active portion, a stepped
resistance profile results which maximizes resistance in the active
portion of the heater layer.
When the flow passage 23 (FIG. 1) is electrically conductive, it is
connected to the power supply by two lengths of heating wire,
preferably copper, which are bonded directly onto the capillary 23
(not shown) for resistive heating. A heating layer is not necessary
in this case because the flow passage 23 itself acts to conduct
heat.
The power supply 29 is sized to provide sufficient power for the
heating element 27 that heats the portion of the flow passage 23.
The power supply 29 is preferably replaceable- and rechargeable and
may include devices such as a capacitor or, more preferably, a
battery. For portable applications, the power supply is, in a
presently preferred embodiment, a replaceable, rechargeable battery
such as four nickel cadmium battery cells connected in series with
a total, non-loaded voltage of approximately 4.8 to 5.6 volts. The
characteristics required of the power supply 29 are, however,
selected in view of the characteristics of other components of the
aerosol generator 21, particularly the characteristics of the
heater 27. One power supply that has been found to operate
successfully in generating an aerosol from liquid propylene glycol
is operated continuously at approximately 2.5 Volts and 0.8 Amps.
The power supplied by the power supply operating at this level is
close to the minimal power requirements for volatizing propylene
glycol at a rate of 1.5 milligrams per second at atmospheric
pressure, illustrating that the aerosol generator 23 may be
operated quite efficiently.
The aerosol generator 23 may generate an aerosol intermittently,
e.g., on demand, or, as discussed further below, continuously. When
it is desired to generate an intermittent aerosol, the material in
liquid form may be supplied to the portion of the flow passage 23
proximate the heater 27 each time that it is desired to generate
the aerosol. Preferably, the material in liquid form flows from the
source 33 of material to the portion of the flow passage 23
proximate the heater 27, such as by being pumped by a pump 35
(shown by dotted lines).
If desired, valves (not shown) may be provided in line between the
portion of the flow passage 23 proximate the heater 27 and the
source 33 of the material to interrupt flow. Preferably, the
material in liquid form is pumped by the pump 35 in metered amounts
sufficient to fill the portion of the flow passage 23 proximate the
heater 27 so that substantially only the material in that portion
of the flow passage will be volatilized to form the aerosol. The
remaining material in the line between the source 33 of material
and the portion of the flow passage 23 prevents expansion of the
volatilized material in the direction of the second end 31 of the
flow passage.
When it is desired to generate an aerosol intermittently for
medicament inhalation, the aerosol generator 23 is preferably
provided with a breath-actuated sensor 37 (shown by dotted lines),
which preferably forms part of a mouthpiece 39 (shown by dotted
lines) disposed proximate the open end 25 of the flow passage 23,
for actuating the pump 35 and the heater 27 so that material in
liquid form is supplied to the flow passage 23 and the material is
volatilized by the heater. The puff-actuated sensor 37 is
preferably of the type that is sensitive to pressure drops
occurring in the mouthpiece 39 when a user draws on the mouthpiece.
The aerosol generator 23 is preferably provided with circuitry such
that, when a user draws on the mouthpiece 39, the power supply
activates the pump 35 to supply material in liquid form to the flow
passage 23 and the power supply activates the heater 27.
A breath-actuated sensor 37 suitable for use in the aerosol
generator may be in the form of a Model 163PC01D35 silicon sensor,
manufactured by the MicroSwitch division of Honeywell, Inc.,
Freeport, Ill., or an SLP004D 0 4'' H.sub.2O Basic Sensor Element,
manufactured by SenSym, Inc., Milpitas, Calif., for example. Other
known flow-sensing devices, such as those using hot-wire anemometry
principles, are also believed to be suitable for use with the
aerosol generator.
The mouthpiece 39 is disposed proximate the open end 25 of the flow
passage 23 and facilitates complete mixing of the volatilized
material with cooler ambient air such that the volatilized material
condenses to form particles. For medicament delivery applications,
the mouthpiece 39 is preferably designed to permit passage of
approximately 60 100 liters of air per minute without substantial
resistance, such a flow rate being the normal flow for inhalation
from an inhaler. Of course, the mouthpiece 39, if provided, may be
designed to pass more or less air, depending upon the intended
application of the aerosol generator and other factors, such as
consumer preferences. A preferred mouthpiece for a hand held asthma
inhaler is approximately 1 inch in diameter and between 1.5 and 2
inches in length, with the open end 25 of the flow passage 23
centered at an end of the mouthpiece.
Depending on the desired aerosol droplet size, a spacer chamber 38
may be added at the open end 25 of the flow passage 23 before the
mouthpiece 39 (see FIG. 1A). The spacer chamber 38 functions in a
manner opposite to known spacer chambers used in aerosol
generators, which reduce particle size by allowing evaporation of
the propellent entraining the material to be delivered. The aerosol
generator described herein produces extremely small (e.g.,
submicron sized) particles and the spacer chamber functions to
increase the average MMAD of the particles. Larger particles may be
desired for various applications, such as medicament delivery
wherein the use of larger particles would decrease the risk of
exhalation of the particles before settling within the lungs of a
patient, for example.
The use of a spacer chamber 38 with the aerosol generator described
herein unexpectedly can increase the particle size from an average
size of .ltoreq.0.50 .mu.m to greater than 0.50 .mu.m, preferably
to at least about 1.0 .mu.m or greater, and more preferably to
about 1.0 5.0 .mu.m. While not wishing to be bound by theory, it is
believed the particles collide with one another in the spacer
chamber over time, allowing growth of the aerosol particles through
coagulation, aggregation and/or coalescence of the particles. The
resultant particle size is determined by the size and shape of the
spacer chamber 38, as well as the amount of time during which the
particles are located therein. These factors may also affect the
amount of particles deposited within the spacer chamber 38.
An increase in the length of time in which the particles are within
the spacer chamber 38, or a decrease in the internal volume of the
spacer chamber 38, both result in larger particle sizes of the
emitted aerosol. The particles generally have a narrow MMAD
distribution. However, the MMAD distribution can be increased by
holding the particles in the spacer chamber 38 for a longer period
of time, or by increasing the size of the spacer chamber 38. Thus,
dependent upon the length of time for which the particles are held
in the spacer chamber 38, or the size of the spacer chamber 38, a
more homogeneous or a more heterogeneous mixture of particle sizes
within a desired range can be obtained. Each spacer has a critical
holding time beyond which the particle size distribution does not
significantly change, or ceases to change, and therefore the
aerosol particle size is stable. See Example 6 and FIG. 9.
The optimum spacer chamber size and shape can be selected based on
the material to be delivered, the desired particle size, and the
configuration of the aerosol generator itself, including the
material used for the flow passage, the characteristics of the
power supply and heater, and/or other like factors. It should be
noted that the smaller the spacer chamber size, and therefore the
larger the particles generated, the more likely the particles are
to deposit within the spacer chamber itself. Therefore, as larger
particles are generated, more particles are lost to the spacer
chamber and therefore are not available for delivery to the desired
target site.
An aerosol generator 121 according to another embodiment of the
present invention is seen with reference to FIG. 3. The basic
components of the aerosol generator 121 are substantially the same
as the components of the aerosol generator 21 shown in FIG. 1, the
aerosol generator 121 shown in FIG. 3 including a presently
preferred liquid material supply assembly 141. The aerosol
generator 121 includes a flow passage 123 having an open end 125, a
heater 127 attached to a portion of the flow passage 123 proximate
the open end, and a power supply 129 for supplying power to the
heater.
A second end 131 of the flow passage 123 extends to a reservoir or
source 133 of liquid material, such as a cylinder of a syringe, and
the liquid material is delivered to the flow passage through the
second end 131 thereof by means of a pump 135, such as a piston of
the syringe. A mouthpiece 139 and breath-actuated sensor 137 (both
shown by dotted lines) may be provided as well, in substantially
the same manner as discussed above with regard to the aerosol
generator 23.
As with aerosol generator 23, it is preferred that the flow passage
123 have an electrically conductive sleeve at the open end 125, or,
more preferably, that the flow passage 123 itself be electrically
conductive. Further, a spacer chamber may be provided between the
open end 125 of the flow passage and mouthpiece 139, as described
with regard to aerosol generator 23.
The illustrated syringe pump 141, including the cylinder 133 and
piston 135, facilitates delivery of liquid material to the flow
passage 123 at a desired flow rate. The syringe pump 141 is
preferably provided with an assembly 143 for automatically moving
the piston 135 relative to the cylinder 133. The assembly 143
preferably permits incremental or continuous advancement or
withdrawal of the piston 135 from the cylinder 133, as desired. If
desired, of course, the piston 135 may alternatively be manually
compressible.
The assembly 143 preferably includes a rod 145, at least a portion
of which is externally threaded. Preferably, the rod 145 is
attached at one end to a shaft 147 of a reversible motor 149,
preferably an electric motor, such that operation of the motor
causes the rod to rotate clockwise or counterclockwise, as desired.
The rod 145 is preferably attached to the shaft 147 by means of a
coupling 151 that permits axial movement of the rod relative to the
shaft, but not rotational movement of the rod relative to the
shaft.
An end of the rod 145 is attached to the piston 135. The rod 145 is
preferably attached to the piston 135 by means of a bearing
assembly 153 such that rotation of the rod does not cause rotation
of the piston. However, if desired, the rod may be rigidly attached
to the piston. The externally threaded portion of the rod 145
extends through an internally threaded opening 155 in a member 157,
which may simply be a nut, which is fixed in position relative to
the motor 149 and the cylinder 133, both of which are preferably
also fixed in position.
Preferably, when the motor 149 is operated, the shaft 147 turns the
rod 145 and the rod turns in the opening 155 relative to the fixed
member 157. As the rod 145 turns in the opening 155, the end of the
rod attached to the piston 135 is advanced or withdrawn from the
cylinder 133, depending upon the thread of the rod and the opening
and the direction in which the rod is turned. The coupling 151
permits the rod 145 to move axially relative to the shaft 147.
Sensors (not shown) are preferably provided to ensure that the rod
145 is not moved excessively into or out of the cylinder 133. It
will be appreciated that a liquid supply arrangement such as the
above-described syringe pump 141 is well suited to supply liquid at
a rate of 1 milligram/second or greater, as needed, and that,
provided a sufficiently powerful heater 127 is provided, an aerosol
may be continuously produced at a rate of 1 milligram/second or
greater, which is understood to be a much greater rate of delivery
of particles in sizes between 0.2 and 2 microns mass median aerosol
diameter than is available with conventional aerosol medicament
delivery systems.
It will often be desirable to minimize contact of the liquid in the
cylinder 133 with oxygen, such as to avoid contamination or
decomposition. To this end, the aerosol generator 121 is preferably
provided with an arrangement for conveniently refilling the
cylinder 133 of the syringe pump 141, such as a line or tube 159
having a valve 161 that may be opened as the piston 135 is
withdrawn in the cylinder to draw liquid from another source of
supply. Another valve 163 may be provided in the flow passage 123
to ensure that liquid flowing into the aerosol generator is charged
into the cylinder and not inadvertently wasted by flowing out of
the open end 125 of the flow passage. If desired, a three-way valve
may be provided to alternatively permit flow from the cylinder 133
to the flow passage 123 and from the line 159 to the cylinder.
In addition, or in the alternative, the cylinder 133 and piston 135
may be configured to be easily replaced when emptied, such as by
providing appropriate fittings where the end of the cylinder meets
the second end 131 of the flow passage 123 and where the rod 145 is
attached to the piston. A new, preferably hermetically sealed,
piston 135 and cylinder 133 can be provided to replace a used
piston and cylinder. Such an arrangement may be particularly
desirable in applications such as hand held inhalers and the
like.
The aerosol generator 121 may continuously generate an aerosol,
such as by continuously operating the motor 149 and the heater 127
such that liquid material is continuously supplied to the flow
passage 123 and the supplied liquid material is continuously
volatilized. In addition, or in the alternative, the aerosol
generator may intermittently generate an aerosol, such as by
intermittently operating the motor 149 and the heater 127 such that
a desired amount of liquid material is supplied to the flow passage
123 over a period of time and the heater is operated for a
sufficient length of time to volatilize the supplied liquid, the
motor and the heater thereafter being turned off. Intermittent
operation in medicament delivery applications is preferably
achieved by actuation of the motor 149 and the heater 127 by the
breath-actuated sensor 137 in combination with appropriate
interconnecting circuitry. Alternative actuating devices, e.g.,
push buttons, may, of course, be used.
An aerosol generator 221 according to another embodiment of the
present invention is seen with reference to FIG. 4. The aerosol
generator 221 includes two or more separate aerosol generators,
which may be substantially the same as the aerosol generator
described above, in combination. The parallel aerosol generator
arrangement facilitates forming a combination aerosol formed by
mixing together two or more separately generated aerosols. The
parallel aerosol generator arrangement is particularly useful where
it is desired to form an aerosol comprising two or more materials
which do not mix well in liquid form.
Each aerosol generator preferably includes a flow passage 223' and
223'', respectively, each flow passage having an open end 225' and
225'', respectively. Heaters 227' and 227'' are preferably provided
for each flow passage 223' and 223'', respectively, although, in
some applications, it may be convenient or possible to provide a
single heater for heating both flow passages. The heaters are
powered by power supplies 229' and 229'', respectively. If desired,
a single power supply may be used to power both heaters.
Each flow passage 223' and 223'' is connected at its second end
231' and 231'', respectively, to sources 233' and 233'',
respectively, of first and second liquid materials. The first and
second liquid materials are advanced into the flow passages 223'
and 223'' by pumps 235' and 235'', respectively. The pumps 235' and
235'' may pump the first and second liquids at the same or
different flow rates, as desired or necessary, and may be driven by
separate driving means or by a common driving means, such as by the
above-described automatic moving assembly. When the first and
second liquid materials in the flow passages 223' and 223'' are
volatilized by the heaters 227' and 227'', respectively, and expand
out of the open ends 225' and 225'' of the flow passages,
respectively, the volatilized first and second materials are mixed
together in a mixing chamber, such as a mouthpiece 239 or a spacer
chamber (not shown), and mix with ambient air so that they condense
and form an aerosol. A breath-actuated sensor 237 may be used to
actuate components such as the one or more power supplies and one
or more motors for driving the pumps.
Where liquids are conveniently miscible, it may also be desirable
to combine, e.g., two or more liquids in one or more flow passages
or a manifold in a location between a source 233' and 233''' of the
liquids and a portion of the flow passage that is heated by the
heater. The liquids may be supplied together to the flow passage
223' from the sources 233' and 233''' by separate pumps 235' and
235''', respectively, at the same or different flow rates, as
desired or necessary, and the pumps may be driven by separate or
common driving means. The heater 227' heats the flow passage 223'
to a temperature sufficient to volatilize the mixed liquid
materials, the volatilized mixed liquid materials expanding out of
the open end 225' of the flow passage and condensing to form a
combination aerosol. If desired, the combination aerosol formed of
the pre-mixed liquids may be combined with other aerosols to form
still further combination aerosols.
The characteristics of the aerosol generated by the aerosol
generator according to the present invention are generally
functions of various parameters of the aerosol generator and the
liquid material supplied to the aerosol generator. For aerosols
intended for inhalation, for example, it is desirable for the
aerosol to be at approximately body temperature when inhaled and
for the mass median aerosol diameter of particles of the aerosol to
be less than 2 microns, preferably between 0.2 and 2 microns, and
more preferably between 0.2 and 1 micron.
It has been observed that liquid materials such as propylene glycol
and glycerol can be formed into aerosols having mass median aerosol
diameters and temperatures in the preferred ranges. While not
wishing to be bound by theory, it is believed that the extremely
small mass median aerosol diameters of the aerosol according to the
present invention are achieved at least in part as a result of the
rapid cooling and condensation of the volatilized material that
exits the heated flow passage. Manipulation of parameters of the
aerosol generator such as the internal diameter of the flow
passage, heat transfer characteristics of the flow passage, heating
capacity of the heater, and the rate at which material in liquid
form is supplied to the flow passage may affect aerosol temperature
and mass median aerosol diameter.
Certain components in solid, i.e., powdered, form may be mixed with
a desired liquid component so that the resulting solution is formed
into an aerosol in the manner described above. Where the solid
component is of the type that remains suspended in the particular
liquid component used, the solid component is forced out of the
open end of the flow passage with the volatilized liquid component.
The resulting aerosol consists of particles resulting from the
condensation of the volatilized liquid and solid component
particles. When volatilized solid component particles are larger or
smaller than the particles resulting from the condensation of the
volatilized liquid component, the resulting aerosol may separate
into its solid and liquid component over time, allowing separate
deposition of the liquid and solid aerosolized components.
It is theorized that improved delivery of the aerosol will result
from the solid component particles and liquid component particles
having approximately the same MMAD once volatilized. To achieve the
same volatilized particle size of the solid component and liquid
component particles, covolatilization and cocoalecense of the solid
and liquid are preferred.
While not wishing to be bound by theory, it is believed that the
separation or covolatilization of the solid component and liquid
component are an effect of the temperature and pump rate of the
aerosol generator as well as of the physical characteristics such
as melting point and boiling point of the solid component and
liquid component and the mutual solubility profile of these
ingredients as a function of the temperature to which they are
heated. Assuming that a constant flow rate and temperature of the
aerosol generator are desired, a like particle size between the
aerosolized solid component and liquid component can best be
achieved by altering either the solid component or liquid component
used.
In the following examples, observations and test results using
benzil and budesonide as solid components in the liquid components
(which may be solvents or vehicles) of propylene glycol and
triethylene glycol are discussed. The trends observed for these
solid components and liquid components are expected to hold true
for other combinations of materials.
Budesonide has a higher melting point than benzil. When used with
propylene glycol as a solvent, aerosolized budesonide and propylene
glycol have a different MMAD, while aerosolized benzil and
propylene glycol have approximately the same MMAD. When triethylene
glycol is the solvent, aerosolized benzil and triethylene glycol
have approximately the same MMAD, and aerosolized budesonide and
triethylene glycol have approximately the same MMAD. Thus, while
not wishing to be bound by theory, it is believed that a solid
which has a higher melting point, and therefore lower volatility,
such as budesonide, requires a solvent having a higher molecular
weight, such as triethylene glycol, in order to achieve
covolatilization and cocoalescence of the solid component and
solvent or vehicle.
A method for generating an aerosol according to the present
invention will now be described with reference to the aerosol
generator 221 shown in FIG. 4. A material in liquid form is
supplied to the flow passage 223' having the open end 225'. The
material supplied to the flow passage 223' is heated by the heater
227' to a temperature sufficient to volatilize the supplied
material such that the volatilized material expands out of the open
end 225' of the flow passage. The volatilized material condenses
upon mixing with ambient atmospheric air, preferably in a
mouthpiece 239, to form the aerosol.
Material may be intermittently supplied to the flow passage 223'
and the supplied material may be intermittently heated to a
temperature sufficient to volatilize the material by intermittently
operating the heater 227' and the pump 235'. The breath-actuated
sensor 237 may be used to intermittently actuate the heater 227'
and the motor 245' for driving the pump 235' when a user draws on
the mouthpiece 239. The pump 235' and the heater 227' may, however,
be manually actuated, e.g., by a push button arrangement and
appropriate circuitry. It will further be appreciated that the pump
235' and the heater 227' may be automatically actuated. For
example, the pump 235' and the heater 227' may be actuated by a
timer for periodic introduction of a medicament in aerosol form to
a patient on a respirator. The pump 235' and the heater 227' may,
further, be continuously operated to continuously form an
aerosol.
If desired, a second material in liquid form may be supplied from a
source of the second material 233'' to a second flow passage 223''
having an open end 225''. The second material supplied to the
second flow passage 223'' is heated by a separate heater 227'' to a
temperature sufficient to volatilize the supplied second material
such that the volatilized second material expands out of the open
end 225'' of the second flow passage. If desired, the second
material supplied to the second flow passage 223'' may be heated by
the same heater 227' that heats the first flow passage 223'. The
volatilized first material and the volatilized second material that
expand out of the open ends of the flow passage 223' and the second
flow passage 223'', respectively, are mixed together with ambient
air such that the volatilized material and the volatilized second
material form first and second aerosols, respectively. The first
and second aerosols are mixed with each other to form a combination
aerosol including the first and second aerosols. The mixing of the
first and second volatilized materials with each other and with air
to form the first and second aerosols and the combination aerosol
preferably takes place in a mixing chamber which, in the case of
aerosol generators for medicament delivery, is preferably the
mouthpiece 239 or a spacer chamber.
In addition to, or as an alternative to, mixing the first and
second aerosols as described above, if desired, a third material in
liquid form may be supplied from a third source 233''' of liquid
material to, e.g., the flow passage 223', together with the first
material. The first material and the third material supplied to the
flow passage 223' are heated by the heater 227' to a temperature
sufficient to volatilize the first material and the third material
such that the volatized first material and third material expand
out of the open end 225' of the flow passage together.
Solid particles may be suspended in solution in the liquid
component supplied from the source of material. When the liquid
component including the suspended solid particles is heated by a
heater, the solid particles are forced out of the open end of the
flow passage as the volatilized liquid component expands such that
the aerosol includes condensed particles of the liquid component
and the solid particles. The solid component, when suspended in
solution, may be of a larger or smaller average diameter than
particles of the liquid component in aerosol form, or may be
approximately the same size. Moreover, the solid particles, when
they form a part of the aerosol, may be of a larger or smaller
average diameter than particles of the liquid component in aerosol
form or may be approximately the same size.
It will be appreciated that embodiments of the aerosol generator
according to the present invention may be fairly large, such as a
table-top mounted item, but may also be miniaturized to be hand
held. The ability of the aerosol generator to be miniaturized is,
in large part, due to the highly efficient heat transfer between
the heater and the flow passage which facilitates battery operation
of the aerosol generator with low power requirements.
EXAMPLES
The Examples were conducted with the apparatus and in the methods
described below unless otherwise indicated.
For purposes of performing experiments in connection with the
aerosol generator described herein, a laboratory unit was designed
which contained the basic elements of the generator, but which was
modular in construction so that the various components could be
exchanged after running. During most of the runs it was possible to
measure the surface temperature of the heater and the power
applied. Mass median aerosol diameter was obtained using a cascade
impactor in accordance with the methods specified in the
"Recommendations of the USP Advisory Panel on Aerosols on the
General Chapters on Aerosols (601) and Uniformity of Dosage Units
(905)," Pharmacopeial Forum. Vol. 20, No. 3, pp. 7477 et. seq. (May
June 1994), and aerosol mass was measured gravimetrically or
chemically by HPLC as collected from the impactor.
In the Examples that follow, the aerosol generator included a flow
passage of a section of fused silica capillary tubing, more
particularly, a phenyl-methyl deactivated capillary guard column
for gas chromatography, available from Restek Corporation,
Bellefonte, Pa., which was carefully wrapped with a 0.008'' OD,
13.1 ohms per foot, heating wire, marked K-AF, available from
Kanthal Corp., Bethel, Conn., to form a 1.0 to 1.5 cm long heating
zone. The wire was wrapped in a fashion that produced close, tight
coils to insure good heat transfer to the flow passage. The point
of the needle of a Model 750N 500 microliter syringe, available
from Hamilton Company, Reno, Nev., was cut off and smoothed to
yield a blunt end. The blunt end was connected to the flow passage
using common gas chromatography capillary column hardware. Either a
ceramic or quartz capillary (1/4'' inner diameter), slotted for
electrical connections, was placed around the heated zone for
insulation.
Alternatively, the aerosol generator included a stainless steel
sleeve on the flow passage of a fused silica capillary tubing. The
sleeve was a stainless steel sleeve of 2 mm length, 24 gauge (0.014
inch) internal diameter, 0.024 inch outer diameter and 0.005 inch
wall thickness, such as that supplied by Small Parts Inc, Miami
Lakes, Fla. (Cat # HTX-24TW-24, Hypo Tube 304 S/S 24 Ga--thin
wall), placed around the fused silica capillary flow passage. The
flow passage alternately comprised a stainless steel tube which was
1.4 1.5 cm long, 32 gauge (0.004 inch) internal diameter and 0.009
inch outer diameter with a 0.0025 inch wall thickness, such as that
supplied by Small Parts Inc, Miami Lakes, Fla. (Cat # HTX-32TW-24,
Hypo Tube 304 S/S 32 Ga--standard wall). When the flow passage was
stainless steel, no separate heating layer was necessary as the
current used to generate heat may be supplied directly through the
metallic flow passage which may be directly or indirectly attached
to a power source.
The syringe body was loaded onto a Model 44 programmable syringe
pump, available from Harvard Apparatus, Inc., South Natick, Mass.
The end of the flow passage was centered and supported inside a
mouthpiece that was machined for mating to the induction port that
connected to a MOUDI model 100 cascade impactor, available from MSP
Corporation, Minneapolis, Minn., as per the "Recommendations of the
USP Advisory Panel on Aerosols on the General Chapters on Aerosols
(601) and Uniformity of Dosage Units (905)," Pharmacopeial Forum.
Vol. 20, No. 3, pp. 7477 et. seq. (May June 1994).
Electrical connections were made to the heater wire leads from a
model TP3433A triple output DC power source, manufactured by Power
Designs, Inc., Westbury, N.Y., and a microminiature open junction
thermocouple was gently placed against one turn of the heater coil
about midway along the heated zone. Computer controlled solid state
switches were used to precisely time the start of the syringe pump
with the power to the heater wire. Power and temperature
measurements were recorded every tenth of a second by a computer
using LAB TECH NOTEBOOK software, available from Laboratory
Technologies, Wilmington, Mass., and a DT2801 I/O board, available
from Data Translation, Inc., Marlboro, Mass.
The cascade impactor was operated according to the manufacturer's
specifications. All runs were conducted with an impactor air flow
rate of 30 liters per minute and a total aerosol production of less
than 100 mg. A loading of 30 to 60 mg in the impactor gave fairly
consistent results.
During the following runs, it was desired to apply sufficient power
to the heater to heat the fluid in the flow passage so that it
reached its boiling point and vaporized before it exited the flow
passage. It was further desired to heat the vapor sufficiently to
prevent condensation at the exit of the flow passage. There were
losses to the surrounding environment which should be considered in
the power equation, and these losses were and are device and
device-design dependent.
In practice, with the particular aerosol generating device used
during the following runs, the device was operated several times to
determine the power required to hold the heater at a specific
temperature in order to determine the losses to the surroundings.
To obtain a rough estimate of total power required, the theoretical
amount of energy required for heating and vaporization was added to
the loss power. Several trial runs were performed to visually
observe the vapor exiting the flow passage and the aerosol
formation. When no condensation at the open end of the flow passage
was seen, then the power was adjusted down until condensation
occurred, after which enough additional power was added so that the
device was operated just above the condensation threshold. It is
contemplated that numerous refinements will be made to commercial
aerosol generating devices and to the manner in which power levels
are set and controlled in such devices.
The following examples reflect various runs performed with an
aerosol generator set up and operated as described herein, unless
otherwise indicated.
Certain abbreviations or terms used within the Examples are set
forth below. Other abbreviations used, unless otherwise indicated,
have the meaning set forth elsewhere herein, or the ordinary
meaning in the art.
TABLE-US-00001 ACI = Andersen cascade impactor CAG = capillary
aerosol generator BUD = budesonide capillary holder = aerosol
generator apparatus HPLC = High Performance Liquid Chromatography
impactor or device for measuring the size of emitted particles
cascade impactor = (simulates lung deposition) MMAD = mass median
aerosol diameter n = number of experimental runs made PG =
propylene glycol SD = standard deviation sec. = seconds TEG =
triethylene glycol throat = simulated passageway for emitted
aerosol particles which connects the aerosol generation device with
the impactor USP = United States Pharmacopeia
The schematic diagram of FIG. 14 depicts the general experimental
set-up for sampling aerosols using an aerosol generator 300
emitting an aerosol into (a) a USP throat 302 or (b) a large volume
spacer chamber box 304 atop a cascade impactor 306. Experiments and
results are set forth below.
Flow Passage Tests
1. Stainless Steel vs. Glass Flow Passage with Glass Spacer
Chamber
Budesonide spacer chamber deposition and aerosol particle size
distribution of aerosols generated using a glass and stainless
steel flow passage, respectively, were compared. The test solutions
used for these experiments was 0.8% w/w budesonide in propylene
glycol. Aerosols were generated and collected in a 500 ml glass
spacer chamber for a period of 20 seconds. The glass spacer chamber
was then connected to an Andersen cascade impactor (ACI) and the
aerosol was sampled at a volumetric flow rate of 28.3 L/min.
Washings were then collected from budesonide deposition sites and
the mean (SD) particle size distribution of the aerosol was
determined. As shown below, the budesonide particle size
distribution for aerosols generated using the standard glass flow
passage and the stainless steel flow passage were similar. In
contrast, the observed deposition of budesonide in the glass spacer
chamber was significantly reduced following aerosol generation
using the stainless steel flow passage. This represents a
significant improvement to the aerosol generator because it
increases the amount of budesonide that is potentially
respirable.
TABLE-US-00002 BUD deposition in BUD Flow Passage spacer chamber
MMAD Glass capillary (n = 5) 43.5 (10.7) .mu.g 1.4 (0.1) .mu.m
Stainless steel capillary (n = 7) 5.07 (2.3) .mu.g 1.2 (0.2)
.mu.m
2. Stainless Steel vs. Glass Flow Passage with Stainless Steel
Spacer Chamber (USP Throat)
Budesonide in propylene glycol aerosol (0.8% w/w) was sampled
directly into an Andersen cascade impactor via a USP stainless
steel throat following generation using a stainless steel or glass
flow passage, respectively. Aerosols were generated for a period of
20 seconds and sampled directly into the impactor via the throat
entrance port at a volumetric flow rate of 28.3 L/min. Washings
were then collected from budesonide deposition sites and the mean
(SD) particle size distribution of the aerosol was determined.
Similar-budesonide particle size distributions for aerosols
generated using the standard glass flow passage and the stainless
steel flow passage were observed, as shown below. The observed
deposition of budesonide in the stainless steel throat was
significantly reduced following aerosol generation using the
stainless steel flow passage as compared to the glass flow passage.
This represents a significant improvement to the aerosol generator
as this increases the amount of budesonide that is potentially
respirable.
TABLE-US-00003 BUD deposition in BUD Flow Passage spacer chamber
MMAD Glass capillary (n = 11) 24.6 (15.9) .mu.g 0.33 (0.1) .mu.m
Stainless steel capillary (n = 4) 0.7 (0.95) .mu.g 0.32 (0.1)
.mu.m
The exact mechanism of the resultant altered solid component
aerosol deposition following budesonide aerosol generation using
the stainless steel flow passage versus a glass flow passage is
unknown. While not wishing to be bound by theory, it is believed
that there is a change in the electrostatic charge on the
budesonide particles during aerosol generation using the glass and
stainless steel flow passages, respectively, which results in less
deposition in the spacer chamber when using a stainless steel flow
passage.
3. Stainless Steel Sleeve
A stainless steel sleeve as described earlier herein was placed
around the tip of a glass capillary flow passage from which an
aerosol was emitted, forming an electrically conductive sleeve on
the flow passage.
Comparative Examples A and B below were performed using a glass
flow passage. Examples C and D were performed with the electrically
conductive sleeve around the glass flow passage.
TABLE-US-00004 TABLE 1 % on Experimental Capillary % in % in
Example Test solution Apparatus Holder Throat Impactor Comparative
0.73% budesonide in Cascade impactor 24.1 (6.6) 14.4 (9.5) 61.5
(6.6) Example A propylene glycol Comparative 0.8% benzil in Cascade
impactor 8.9 (6.2) 26.7 (3.4) 65.3 (8.8) Example B propylene glycol
**Example 0.8% budesonide in Cascade impactor 0.4 (0.6) 12.3 (7.9)
87.2 (7.5) C propylene glycol **Example 0.8% budesonide in Cascade
impactor 0.6 (0.5) 24.9 (9.5) 74.4 (9.7) D propylene glycol and
spacer chamber* *A large volume spacer chamber (6.3 L plexiglass
box) was used to collect the aerosol prior to sampling into the
Moudi cascade impactor. **Sleeve present.
As can be seen from the above data (mean.+-.SD deposition), the use
of an electrically conductive metal sleeve around the sleeve of the
glass flow passage significantly and reproducibly reduces the
amount of material deposited in or on the aerosol generator itself
(capillary holder), and greatly increases the amount of material
delivered to the target site as represented by the impactor.
Spacer Chamber Tests
For the following examples, the CAG was run with a silica (glass)
capillary flow passage. Statistical comparisons were made where
appropriate using a paired t-test, as known in the art.
Significance was assessed at the 95th percentile for probability. A
minimum of five replicates of each experiment was performed and
means (.+-.standard deviation) are presented. The mass median
aerodynamic diameter (D50) was defined as the particle size at the
50th percentile on a cumulative percentage mass undersize
distribution. In many cases, the MMAD was determined automatically
by the Aerosizer Time-of-Flight Spectrometer (Amherst Process
Instruments, Hadley, Mass.). In other cases, a cascade impactor was
used as described elsewhere herein.
4. Effect of using a Large Volume Spacer Chamber on the Aerodynamic
Particle Size Distribution of Aerosol
0.4% w/v benzil (BZ) dissolved in propylene glycol (PG) aerosols
were produced, and drawn through the cascade impactor via two
different entrance ports. The first was a plexiglass 90.degree. USP
throat (approx. volume 80 ml). This entrance port was used in
control experiments. The second was a large volume plexiglass
spacer chamber (approx. volume 6.3 L). Aerosol fired into the
entrance ports was sized using the MOUDI cascade impactor (MSP
Corporation, Minneapolis, Minn.) operating at 30 L/min. Five
experiments were performed for both entrance ports. Particle size
distributions were measured as the total mass distribution of
propylene glycol and benzil, determined gravimetrically. The mass
distribution of benzil alone was determined by HPLC.
The results as shown in FIG. 5 demonstrate that use of the spacer
chamber increased both the mean MMAD (error bars are SD) of the
aerosol particles comprising aerosolized benzil and propylene
glycol, as determined gravimetrically, and of the aerosolized
benzil particles, as determined by HPLC assay.
5. Effect of Holding Time on the Aerosol Particle Size Distribution
using a Large Volume Spacer Chamber (6.3L)
The effect of holding time on particle size distribution within a
sealed spacer chamber was characterized using the Aerosizer
Time-of-Flight Spectrometer (Amherst Process Instruments, Hadley,
Mass.). Equivalent bolus amounts of propylene glycol were
aerosolized and infused into a large volume plexiglass spacer
chamber (approx. 6.3L) and sealed inside for durations of 10 sec.,
100 sec., 200 sec., and 300 sec. Sampling into the Aerosizer was
performed after these times. Five experiments were performed for
each holding time.
The results, as shown in FIGS. 6 and 7 (expressed as mean
results.+-.standard deviations), demonstrate the increase in MMAD
of the particles over time.
6. Effect of Spacer Chamber Volume and Holding Time on the
Aerodynamic Particle Size Distribution of CAG Aerosol
A study was performed on the effect of spacer chamber volume on
aerodynamic particle size distribution for propylene glycol
aerosols with initially comparable aerodynamic size distribution
and concentration. Glass conical spacer chambers of volumes 125 ml,
500 ml, 2000 ml and 6300 ml were used. Holding times of propylene
glycol aerosol within the spacer chambers were 10 sec., 100 sec.,
200 sec. and 300 sec. in duration prior to sizing. Five experiments
were performed for each spacer chamber at each of the holding
times. Sizing was again performed with the Aerosizer Time-of-Flight
Spectrometer.
The mean results (.+-.SD) shown in FIG. 8 demonstrate the increase
in MMAD of the particles with decreasing spacer chamber size,
following a holding time of 10 sec. FIG. 9 reveals the effects of
spacer chamber volume over a series of holding times. As shown in
FIG. 9, holding time has little effect on small volume spacer
chambers. However, there is a significant increase in MMAD as a
function of holding time for larger spacer chambers, such as the
2000 ml and 6300 ml spacer chambers. It is observed that the change
in particle size distribution lessens over time, suggesting a
critical holding time beyond which the particle size does not
change significantly for a given spacer chamber size.
7. Comparison of the Aerodynamic Particle Size Distribution of the
Solid Component Particles of Budesonide and Benzil, and the Liquid
Component, Propylene Glycol, when Aerosolized
Table 2 shows the mass distribution of propylene glycol, budesonide
and benzil when sampled via a throat (Comparative Example 1) and
large volume (6.4L) Plexiglass spacer chamber without holding
(Example 1), respectively, into a cascade impactor apparatus as
shown in FIGS. 14A and B. A propylene glycol solution containing
0.4% budesonide and 0.4% benzil was aerosolized for this
experiment.
Lower total mass recovery of propylene glycol reflected deposition
within the spacer chamber. The MMAD of aerosolized propylene glycol
and aerosolized benzil were identical when sampled via the throat
(0.43 .mu.m), however, the MMAD of aerosolized budesonide was
significantly smaller (0.34 .mu.m).
Using the spacer chamber, the aerosol particle size of propylene
glycol and benzil was observed to increase. The MMAD of aerosolized
PG and aerosolized benzil were nearly identical (1.27 .mu.m and
1.28 .mu.m, respectively), while the MMAD for the aerosolized
budesonide particles was <0.2 .mu.m.
In contrast to metered dose inhaler aerosols, which get smaller
when fired through spacer chambers, aerosols generated by the CAG
generally increased in particle size with respect to both the
aerosolized solid component and aerosolized liquid component when
sampled via a spacer chamber.
TABLE-US-00005 TABLE 2 PG BUD Total MMAD BUD Mass BUD Mass BUD Mass
BUD Mass Total Total Capillary Throat or Mass MMAD Recovered Mass
Recovered Holder Spacer Impactor BUD Comparative 24.98 mg 0.43
.mu.m 65.2 .mu.g 12.8 .mu.g 14.3 .mu.g 38.3 .mu.g 0.34 .mu.m
Example 1 (Throat) Example 1 17.04 mg 1.27 .mu.m 65.8 .mu.g 22.1
.mu.g 12.4 .mu.g 31.3 .mu.g <0.2 .mu.m (Spacer) BZ BZ Mass BZ
Mass BZ Mass Total Capillary Throat/ BZ Mass MMAD Recovered Holder
Spacer Impactor BZ Comparative 77.0 .mu.g 2.9 .mu.g 3.1 .mu.g 71.0
.mu.g 0.43 .mu.m Example 1 (Throat) Example 1 69.6 .mu.g 1.7 .mu.g
14.0 .mu.g 53.8 .mu.g 1.28 .mu.m (Spacer)
8. Characterization of the Effect of Spacer Chamber Volume on the
In-Vitro Particle Size Distribution of Budesonide in a CAG
Aerosol
Table 3 summarizes the mass distribution of budesonide following
aerosolization and sampling via a USP throat (Comparative Example)
and sampling via glass spacer chambers with volumes of 2000 ml, 500
ml and 125 ml (Examples 1 3, respectively) using the following
experimental conditions. A 0.75% budesonide in propylene glycol
solution was aerosolized and sized using the Andersen cascade
impactor, at a volumetric flow rate of 28.3 L/min. No holding time
was employed in the throat studies, however a 10 sec. holding time
was used for the spacer studies. Similar conditions and test
solutions were used for each experiment. Budesonide concentration
determinations were made by HPLC.
Experimental recovery of budesonide was comparable for each
experiment, as shown in the columns labeled Total Mass Recovered
and % Theoretical Recovery, with a range of 73.66 86.15% of the
theoretical amount of budesonide being recovered. However, the
regional distribution of budesonide was observed to vary throughout
the apparatus as a function of (1) using a spacer chamber (compared
to the throat) and (2) the volume of the spacer chamber used.
FIG. 10 shows the cumulative percent of solute undersize of
budesonide found in the Comparative Example and Examples 1 3 of
Table 3 versus the budesonide MMAD. The budesonide aerosol
generated using the CAG and sampled via the throat contained about
60% of budesonide particles that were less than 0.4 .mu.m
(Comparative Example). This is an extremely high fraction of
sub-micron particles. Following aerosol generation into the 2000 ml
spacer chamber, the measured mass of particles less than 0.4 .mu.m
was reduced to about 38% of the sampled aerosol (Example 1).
Further reduction in spacer chamber size further reduced the
fraction of sub-micron particles available for inhalation (500
ml=19% (Example 2); 125 ml=11% (Example 3)). This change in
budesonide aerosol particle size distribution is reflected in the
MMAD for these aerosols as shown in Table 3.
The MMAD of the budesonide aerosol sampled via the throat could not
be accurately determined using the Andersen cascade impactor. It
was shown to be less than 0.4 .mu.m. (Previous studies using an
alternative impactor, the MOUDI, have revealed a MMAD for
budesonide sampled via the throat of approximately 0.2 0.3 .mu.m.
The MMAD of budesonide following aerosolization via the 2000, 500
and 125 ml spacer chambers was 0.81 .mu.m, 1.40 .mu.m and 2.37
.mu.m, respectively.
These experiments indicate that appropriate selection of a spacer
chamber volume allows the particle size distribution of the solid
component (budesonide) and liquid component (propylene glycol) to
be manipulated. Those skilled in the art will also recognize that
different spacer chamber shapes as well as volumes may influence
these results further. This allows aerosols of various particle
size distributions to be produced to target regional deposition of
medicaments within the lung by using a combination of the CAG and a
suitable spacer chamber volume and design.
TABLE-US-00006 TABLE 3 BUDESONIDE Total Mass Mass in Mass in Mass
in Impactor Throat or Spacer Capillary % Recovered Impactor Spacer
or Capillary MMAD % of Chamber Holder Theoretical (.mu.g) (.mu.g)
Throat (.mu.g) Holder (.mu.g) (.mu.m) Total % of Total % of Total
Recovery Comparative 181.63 155.72 24.65 1.22 <0.4 85.47 13.81
0.69 86.15 Throat Example Example 1 162.95 116.78 41.19 4.82 0.81
71.85 24.87 3.20 77.29 2000 ml Example 2 155.29 102.55 43.54 9.21
1.40 66.64 28.23 5.13 73.66 500 ml Example 3 164.27 66.88 94.40
2.55 2.37 40.98 57.20 1.55 77.92 125 ml The results of Table 3 are
shown graphically in FIG. 10.
Solvent Tests
9. The Following Examples were Performed using a Silica Capillary
Flow Passage.
Preliminary aerosol generation studies using benzil as a model
solute (solid or liquid component) dissolved in a propylene glycol
vehicle and generated as an aerosol using the CAG revealed a
pattern of co-evaporation and co-condensation of solute and
vehicle. The phenomenon called co-condensation is defined as
indicating that the aerodynamic particle size distribution of the
vehicle and solute are identical when collected and measured using
a cascade impaction method. The total mass distribution of the
aerosol determined gravimetrically can essentially be considered to
be the vehicle distribution because the vehicle represents 99.6% of
the aerosol mass. The distribution of the solute was determined by
specific chemical analysis.
FIG. 11 shows the mean aerodynamic particle size distributions of
BZ, BUD and PG (error bars are standard deviation) following
aerosolization using a CAG. The solution compositions are indicated
in FIG. 11. Co-condensation of vehicle and solute are observed for
BZ in PG, but not for BUD in PG. Table 4 shows the mean mass median
aerodynamic diameters (with standard deviation) of both the total
aerosol and the solute component for the benzil and budesonide
aerosols, respectively.
In an attempt to investigate the mechanism whereby benzil
co-condenses with PG and budesonide does not, an experiment was
performed using a test formulation containing 0.4% w/v of each
solute. Table 4 reveals that when a mixed solute system, i.e., a
system with more than one dissolved component, is aerosolized, the
characteristics of condensation of the individual solutes were
unaltered. That is, benzil co-condensed with propylene glycol,
while budesonide was observed to have a significantly lower MMAD
compared to the propylene glycol vehicle.
As an alternative to propylene glycol, the aerosol characteristics
of budesonide and benzil solid component aerosols in triethylene
glycol (TEG) was tested. Table 4 reveals that there was no
significant difference between the total aerosol MMAD and the
solute MMAD following aerosolization of benzil or budesonide in
triethylene glycol. Co-condensation occurred with both solutes.
FIG. 12 compares the mean aerodynamic particle size distribution
(error bars are standard deviation) of a 0.40% w/v budesonide in
triethylene glycol solution and a 0.40% w/v budesonide in propylene
glycol solution following aerosolization using the CAG.
Co-condensation of budesonide and vehicle was only observed when
budesonide was aerosolized in a triethylene glycol vehicle.
TABLE-US-00007 TABLE 4 Total MMAD in Solute component .mu.m
(Standard MMAD in .mu.m Formulation Deviation) (Standard Deviation)
0.38% w/v Benzil in PG 0.54 (0.05) 0.54 (0.05) 0.73% w/v Budesonide
0.46 (0.02) 0.27 (0.05) in PG 0.4% w/v Benzil and 0.43 (0.01)
Benzil Budesonide 0.4% Budesonide in PG 0.43 (0.01) 0.34 (0.02)
0.4% w/w Benzil in 0.57 (0.05) 0.61 (0.05) TEG 0.4% w/w Budesonide
0.49 (0.06) 0.50 (0.05) in TEG
A preferred embodiment of some CAG aerosols may require
co-condensation of the solute and the vehicle to minimize
exhalation of the resultant sub-micron particles. If the solute,
after aerosolization, is significantly smaller than the aerosolized
liquid component, the aerosolized solute may separate from the
liquid component and be expelled from the patient's lungs before
settling in the target area. Thus, the desired medicament in the
form of the aerosolized solute would not be administered in the
proper location, or in the desired amount, to the patient.
Alternatively, if the solute after aerosolization is larger than
the liquid component, the solute may settle too soon in the lungs
or settle in the back of the mouth or throat of the patient, or in
the aerosol generator, thus diminishing medicament delivery. The
use of triethylene glycol as a vehicle is one mechanism by which
the co-condensation of budesonide aerosols can be effected, thereby
preventing these problems.
Further data regarding the co-condensation, or lack thereof, of
budesonide and benzil in propylene glycol and triethylene glycol is
shown in FIGS. 13 (a d). It is clear from this figure that
aerosolized benzil has approximately the same MMAD as both
aerosolized propylene glycol and aerosolized triethylene glycol
(FIG. 13(a), FIG. 13(b)), while aerosolized budesonide has
approximately the same MMAD as aerosolized triethylene glycol (FIG.
13(d)), but not propylene glycol (FIG. 13(c)).
Those skilled in the art will recognize that some medicaments may
benefit from CAG aerosolization and inhalation without
co-condensation with the vehicle. For example, aerodynamic particle
sizes substantially less than 0.5 .mu.m, such as about 0.1 or 0.2
.mu.m, are known to be deposited homogeneously by aerosol particle
diffusion in the extreme lung periphery. It is feasible that some
medicaments when deposited in such very small sizes from aerosols
having vehicles with a greater MMAD may exhibit substantially
different pharmaceutical and pharmacological or toxicological
properties than medicaments with a MMAD similar to those of the
vehicle.
While this invention has been illustrated and described in
accordance with preferred embodiments, it is recognized that
variations and changes may be made without departing from the
invention as set forth in the claims.
* * * * *